Hydrogenation process



United States Patent HYDRQGENATION PROCESS Joseph Levy, Paramus, N. J., assignor to Nopco Chemical iCompany, Harrison, N. J., a corporation of New ersey No Drawing. Application April 26, 1955, Serial No. 504,085

17 Claims. (Cl. 260-2932) This application is a continuation-in-part of my co-pending application Serial No. 182,127, filed August 29, 1950, now abandoned.

This invention relates to a hydrogenation process and more particularly to a process wherein alkyl or aryl substituted pyridine compounds are hydrogenated to the corresponding alkyl or aryl substituted piperidines.

Processes which disclose the hydrogenation of alkyl or aryl substituted pyridine compounds to produce the corresponding substituted piperidine compounds are quite well known in the art. In the text Heterocyclic Compounds Volume I, edited by Elderfeld and published in 1950 by John Wiley and Sons, Inc., on page 631 it is stated that the preparation of piperidine compounds is accomplished most commonly by the reduction of the corresponding pyridine compounds and that this reduction may be accomplished by means of reagents such as sodium and absolute alcohol, tin and hydrochloric acid or hydrogen in the presence of either nickel or a noble metal catalyst. The author further states that except under special circumstances, catalytic methods have almost entirely replaced the reduction with sodium and alcohols. This statement is borne out by a study of the prior art processes from which it is seen that the most recent hydrogenations have been catalyzed by either platinum oxide or Raney nickel catalyst. In J. A. C. S. 68, 2592 (1946), McElvain and Carney cite a process enumerated in the text Reactions of Hydrogen by Adkins, page 64-67, published by the University of Wisconsin Press, Madison, Wisconsin (1937), wherein substituted pyridine compounds are hydrogenated to the corresponding substituted piperidines using Raney nickel catalyst. This text discloses the hydrogenation of various types of substituted pyridine compounds among which were 2-methyl pyridine and 2,6-dimethyl pyridine. In general, the hydrogenation processes by which these compounds were prepared were high temperaturehigh pressure reactions. The Z-methyl pyridine was reduced in the presence of Raney nickel catalyst to the corresponding substituted piperidine at 200 C. and under a hydrogen pressure of 150 to 300 atmospheres. Such a process, when applied to production on a plant scale, would be economically undesirable because the high temperatures and high pressures therein employed would necessitate the use of equipment of rather elaborate design which, of course, would be quite costly. In the process for the hydrogenation of 2,6-dimethyl pyridine, the 2,6-dimethyl pyridine was dissolved in methylcyclohexane and then reduced to 2,6-dimethyl piperidine at 175 C. under a hydrogen pressure of 150 to 300 atmospheres. This process because of the use of such relatively high pressures also necessitates the use of rather elaborate, hence costly, equipment. These two processes are merely illustrative of general procedures employed in the art. These prior art processes are carried out at rather high temperatures and high pressures when Raney nickel is employed as the catalyst. In J. A. C. S. 50, 2260 (1928), Hamilton and Adams disclose a process wherein pyridine hydrochloride and pyridonium salts are reduced with hydrogen in the 7 Patented Nov. 12, 19 57 ice presence of platinum oxide platinum black. This process, catalyzed by the so called Adams catalyst, permits hydrogenation at low temperatures and relatively low pressures, but the extensive use of this hydrogenation catalyst in large scale production is limited by its excessive cost.

It is the object of this invention to provide an improved process for hydrogenating alkyl and aryl substituted pyridine compounds to the corresponding alkyl and aryl substituted piperidines.

A further object of this invention is to provide a procedure wherein the hydrogenation of alkyl and aryl substituted pyridines can be carried out at low temperatures and relatively low pressures.

Other objects of the invention will in part be obvious and will in part appear hereinafter.

I have discovered that the above and other objects of the invention may be accomplished by dissolving the alkyl or aryl substituted pyridine compound as such or in the form of an acid salt thereof in a suitable solvent and hydrogenating the pyridine compound in the presence of a very large amount of Raney nickel catalyst.

Raney nickel catalyst is a well known hydrogenation catalyst and descriptions of its preparation may be found in U. S. Patent No. 1,628,190 of Raney, in I. A. C. S. 54, 4116 (1932) and in the textbook Organic Synthesis, 21, 15 (1941) published by John Wiley and Sons, Inc., New York. In general, this catalyst is prepared by treating a finely powdered alloy consisting of about 50% aluminum and 50% nickel with a solution of sodium or potassium hydroxide until the aluminum in the alloy is dissolved by the alkali leaving the nickel in a finely divided and highly active form. The nickel is then washed several times with water and finally stored under water or some other suitable solvent until it is to be used. Raney nickel catalyst is relatively quite inexpensive and because of this fact its use, in such a process as this, is highly desirable.

The alkyl and aryl substituted pyridine compounds which can be hydrogenated to the corresponding alkyl and aryl substituted piperidine compounds by the process of the invention are pyridine compounds which are substituted on the 2 or the 6 carbon atom or which are substituted on both the 2 and the 6 carbon atom. Moreover, this process is applicable to substituted pyridine compounds in which the substituted group is either saturated or unsaturated. In the case of the hydrogenation of an alkyl substituted pyridine compound the alkyl group of which is unsaturated, not only will the pyridine ring become saturated but also the unsaturated alkyl group substituted thereon will be converted into the corresponding saturated alkyl group. Analogous to these results are those obtained when an aryl substituted pyridine compound is hydrogenated. In this case, also, not only the pyridine ring portion of the molecule is hydrogenated but the unsaturated aryl group substituted thereon is reduced to the corresponding saturated group. Examples of several such substituted pyridine compounds to which this hydrogenation process is applicable are Z-methyl pyridine, 2,6-dimethy1 pyridine, 2-ethyl pyridine, 2,6-diethy1 pyridine, 2-propyl pyridine, 2-vinyl pyridine, 2,6-divinyl pyridine, 2-propenyl pyridine, 2-benzyl pyridine, 2,6-dibenzyl pyridine, 2-styryl pyridine, etc.

In the process of the invention the substituted pyridine compound is dissolved in a suitable solvent and hydrogenated therein. Solvents suitable for use in the process include water; hydrocarbon solvents such as benzene, toluene, xylene, naphtha, hexane, heptane, etc.; and saturated aliphatic alcohols such as ethyl alcohol, butyl alcohol, isopropyl alcohol, etc., or mixtures of such alcohols with Water in any proportion in which they are miscible with water. The reduction with hydrogen can be run in aqueous solution, in alcoholic solution or in a mixture of water and a water miscible alcohol on the inorganic or organic acid salts, such as the hydrochloride salt, acetate salt, etc., of the alkyl or aryl substituted pyridinesoronthe alkyl pr ar y l'substituted pyridine in the formpf its free base. The reduction can also be runon the alkyl or ar yl substituted pyridine in the form of its r a as hydro ar o ve s. T amoun ofs en laye i net r ic b Q u ssta f c t quan m st Pre e to is' q vath s bst ut d P ri in Pmmd. th r n. t e P efer d. emb ime o h nvehtion, for economy and simpli eity the alkyl or aryl substituted pyridine compound is hydrogenated to the corr ondin l l. .2 uns b tute pe f mpo aawq s ya a ue u so t t ea is, an quesu solution haying 'a pH of from abeut 4.0 to about 7.0. More specifically, the reduction is run preferably in aqueous solution on an acid salt of thesubstifuted pyridine compound- A A very largeamount ofRaney nickelcatalyst is used in the process of the invention At least about one part of Raney nickel catalyst is employed for each two parts pf the substituted pyridine compound to be hydrogenated. Preferably at least about one partof Raney nickel catalyst is employed for each part of the substituted pyridine compound. This is a relatively large quantity of catalyst but the economy or efiiciency of the process is not impaired since the eatalyst is readily recovered and can be reused me o s me. The resu t b a i b dw m in the presence "of the recovered catalyst are just as outstanding those'obtained when a n'shl 'prepared catalyst e is employed. 7 t

l have found that by employing a large amount "of Raney nickel catalyst in the hydrogenation process, the process may be carried out very effi ciently at room temperature and at a relatively low ressure, i. e. at a pressure of from about 2 to about 5 atmospheres, and preferably the hydrogenation is carried out under such madame reaction conditions. If desired, however, the hydrogenation rnay be carried outat temperatures above room temperature and at moderately elevated pressures, e. g. 250 -to 300 lbs. per 'sq. inch. g

It has been stated previously that an alkyl or aryl substituted pyridine compound'in the form'of an inorganic or organic acid salt thereof or as the free base can be reduced in aqueous fm edia, alcoholic rnedia or a wateralcohol mixture and that an alkyl or aryl substituted compound in the form of the free base can be reduced in a hydrocarbon solvent. When it is desired to hydrogenate an inorganic or organic acid salt of the alkyl or aryl substituted pyridine in an aqueous solution, an alcoholic solution, o an aqueous-alcoholic solution thereof, the solution of the substituted pyridine compound isacid'ified to a pH of from about 4.0 to 7.0 with any suitable acid, for example, hydrochloric acid, acetic'acid, etc., and then hydrogenated. 'It is essential in this process that the pH be adjusted within the specified range for optimum elfficiency and results. Furthermore, it is essential that the pH of the solution be maintained above the minimum limit, that is a pH of 4.0, for it has been found that attempts to hydrogenate at a pH which is lower than 4.0 results in the presence of a quantity of free, unreacted acid which will in turn react with and therefore inactivate the catalyst. When the alkyl or aryl substituted pyridine compound is to be hydrogenated in the form of its free base, the compound is completely dissolved in Water, alcohol, mixtures of water and a water miscible alcohol or in a hydrocarbon solvent and then hydrogenated therein. The yields obtained, regardless of whether the hydrogenation is carried out on the substituted pyridine free base or an acid salt of the substituted pyridine in aqueous media, or mixtures thereof or on the substituted-pyridine free base in a hydrocarbon solvent, are excellent.

The product obtained by hydrogenating the substituted pyridine, as the free base or as the acid salt thereof, is readily'liberatedjrom the solution in which it has been hydrogenated. For example ensue saltbf analk'yl "6r 4 aryl substituted pyridine compound can be hydrogenated while dissolved in water, an aliphatic alcohol or a mixture of water and a water miscible aliphatic alcohol. In such a case, upon completion of hydrogenation the solution is filtered to remove the nickel catalyst, then .the solution is acidified to a pH of about 2.0 and finally it is evaporated to dryness. The residual acid salt of the substituted piperidine obtainedby removing the solvent from the solution is then dissolvedin water and the resulting aqueous solution is treated with an alkali or carbonate solution to liberate the substituted piperidine free base. This free base is then isolated from the aqueous solution by extracting it from the aqueoussolution with any suitable solvent following which the'sswfirextract containing the desired free base is dried, e. g. over sodium sulfate, and then the alkyl or aryl substituted piperidine free base is obtained in crude form by removal of the solvent from the solvent extract by evaporation. The substituted piperidine is readilyobtained in a very pure form by means pf fractional distillation of the crude product. When the alkyl or aryl substitutedpyridine is hydrogenated in the form of the free base while dissolved in water, an alcohol, mixtures thereof or in a hydrocarbon solvent, the alkyl or aryl substituted piperidine compound is obtained by first filtering the catalyst from the solution and then treating the solution, in the case of water, alcohol and mixtures thereof with acid to a pH of about 2.0, or in the case of a hydrocarbon sol vent by adding a sufiicient amount {at acid to convert all of the substituted piperidine to its acid salt. The solution is next evaporated to dryness, the residue obtained redissolved in water and finally treated with alkali or carbonate solution, thus causing the 'substituted piperidine free base to separate, usually in the'form of a Water immiscible layer. The free base may then be isolated by extracting it from the water with a suitable waterimmiscible solvent, The solvent is then removed from the solvent extracts by evaporation and the residual liquid fractionally distilled to give the desired substituted piperidine compound in a very pure form.

The outstanding feature of the invention is the fact that by using a very large quantity of Raney nickel catalyst, alkyl or aryl substituted pyridine compounds can be hydrogenated at low temperatures and relatively low pressure. Preferably the alkyl or aryl substituted pyridine compounds are hydrogenated at room temperature. This is an outstanding development in the field since prior art processes wherein alkyl or aryl substituted piperidine compounds areproduced using Raney nickel as the catalyst require the use of temperatures ranging up tofabout 200 C. Also the prior art processes which use -Raney nickel catalyst require'the use of quite'hi'gh pressures for "the hydrogenation reaction. By employing the p'rocessdisclosed herein, however, alkyl or aryl substituted pyridine compounds can be hydrogenated'to alkyl or aryl substituted piperidine compounds at room temperature and underpre'ssures of-about 2 to 5 atmospheres. Of course, if desired, slightly higher temperatures can be used and pressures up to 250-300 lbs/sq. in. can be employed. However, the use of these slightly higher temperatures and pressures is optional and is not necessary.

For a fuller understanding of'the nature and objects of the invention reference may be had to the following examples which are given merely as further illustrations ofthe invention and are not to be construed in a limiting sense.

Example I In this example, 9.3 grams of 2-methy1 pyridine were added to a solution of 6 cc. of glacial acetic acid in 50cc. water. The pH of the solution at this time was about-5.0. The 2'-methyl pyridine in solution was then hydrogenated b'y agitating the solution in an atmosphere of hydrogen at about 4 atmospheres pressure in the presence o f 'abo'ii't 10 grams :of Raney nickel catalyst. When the'reduetioh complete, signified by cessation 'ef hydrogen that tion, the catalyst was filtered from the solution and the filtrate acidified to a pH of about 2.0 with 20 cc. of about 6 N hydrochloric acid. The solution was then evaporated to dryness in vacuo. The residue obtained on the evaporation was 13.61 grams of colorless needles which were the hydrochloride salt of Z-methyl piperidine. This salt had a melting point of 207209 C.

A similar reduction was run using identical quantities of reactants and employing the same conditions for the hydrogenation; The yield from this second hydrogenation was 13.55 grams of the hydrochloride salt of Z-methyl piperidine. The products obtained from the two reductions were combined giving a total of 27.16 grams and treated with 25 cc. of water and 15 cc. of 50% caustic soda solution. The Z-methyl piperidine base was thus liberated forming a separate layer which was readily isolated from the aqueous mixture by extracting the aqueous mixture with ether, drying the ether extracts over sodium sulfate, and then removing the ether from the extracts by evaporation on a steam bath. The residual liquid was then fractionally distilled giving 15.15 grams of 2-methyl piperidine, or 76.5% of theory calculated by weight on the Z-methyl pyridine. The product distilled at l17l17.5 C.

Example 11 In the present example 9.3 grams of 2-methyl pyridine were admixed with about 50 cc. toluene. To this solution about grams of Raney nickel catalyst was added. The 2-methyl pyridine was then hydrogenated by agitating the toluene solution thereof in an atmosphere of hydrogen under a pressure of about 4 atmospheres at room temperature. The reduction was halted when it was about two-thirds complete and an additional 10 grams of Raney nickel catalyst added. The reduction was then continued until hydrogen adsorption ceased signifying completion of the reaction. The solution was then filtered to remove the catalyst therefrom. The filtered solution was treated with about 25 cc. of 6 N hydrochloric acid and was then evaporated to dryness to remove the toluene and any water that might be present. The residue from the evaporation was 11.02 grams of the hydrochloride salt of 2-methyl piperidine. It was in the form of colorless crystals melting at 208210 C. The Z-methyl piperidine free base can be isolated from the hydrochloride salt in the same manner as in Example I.

Example 111 In this example 9.3 grams of 2-rnethyl pyridine were treated with 75 cc. of water having about 8.5 cc. of concentrated hydrochloric acid dissolved therein. The pH of the solution at this time was about 4.0. To this solution were added about 10 grams of Raney nickel catalyst which had previously been employed and subsequently recovered from five similar reductions. The 2-methyl pyridine was then reduced in this solution by agitating the solution in an atmosphere of hydrogen under a pressure of about 4 atmospheres at room temperature. The reduction was excellent with the take up of hydrogen proceeding smoothly and relatively rapidly. When hydrogen adsorption ceased, the catalyst was removed from the solution by filtration. The alkaline solution was next acidified to a pH of about 2.0 with about 20 cc. of 6 N hydrochloric acid and finally evaporated to dryness. The residue obtained from the evaporation was 13.64 grams of the hydrochloride salt of 2-methyl piperidine having a melting point of 207-210 C. This salt can be converted to the free base of Z-methyl piperidine by treatment according to Example I.

Example IV In this example 9.3 grams of Z-methyl pyridine were treated with about 50 cc. of water. To this solution were added about 10 grams of Raney nickel catalyst which had been employed in a previous similar reduction and subsequently recovered. This solution was then agitated at room temperature in an atmosphere of hydrogen under a pressure of about 4 atmospheres to effect the reduction of the 2-methyl pyridine dissolved therein. The reduc tion readily proceeded until the completion of reaction was marked by the cessation of hydrogen adsorption. The solution was then filtered to effect the removal of the nickel catalyst. This solution was next acidified to a pH of about 2.0 with about 20 cc. of 6 N hydrochloric acid and then evaporated to dryness. The residue from the evaporation was 13.67 grams of the hydrochloride salt of Z-methyl piperidine having a melting point of 2082l0 C.

' Example V In this example 21.4 grams (0.2 mol) of 2,6-dirnethyl pyridine were admixed with cc. of water having dissolved therein 15 cc. hydrochloric acid thus giving a solution having a pH of about 4.0. To this solution were added about 25 grams of Raney nickel catalyst and the 2,6-dimethyl pyridine in the solution was then hydrogenated by agitating the solution in an atmosphere of hydrogen under a pressure of about 4 atmospheres at room temperature until hydrogen adsorption ceased. When the reaction was complete the Raney nickel catalyst was removed from the solution by filtration and the alkaline solution was acidified to a pH of about 2.0 with 6 N hydrochloric acid. This solution was then evaporated to dryness. The residue from the evaporation was 28.82 grams of the hydrochloride salt of 2,6-dimethyl piperidine. It had a melting point of 280282 C. This salt can be readily converted to 2,6-dimethyl piperidine free base by treatment according to the process described in Example 1.

Example VI In order to demonstrate the significant effect of the use of the required quantities of Raney nickel catalyst on the reduction of substituted pyridines, three hydrogenations of 2-methyl pyridine were conducted in essentially the same manner as in Example I using amounts of catalyst corresponding respectively to 25%, 43% and 86% of the weight of 2-rnethyl pyridine. It was found that complete reduction occurred only in that procedure in which 86% by weight of catalyst, an amount corresponding approximately to the preferred ratio of one part of Raney nickel catalyst to one part of substituted pyridine compound, was employed. The results observed in this series of reductions are tabulated below:

Percentage Catalyst Period of Hydra geuation Degree of Reduction After about 24 hours in the procedure wherein 43% of catalyst was employed and about 26 hours in the procedure where 25% of catalyst was employed the rate of hydrogen adsorption had become so slow that it was impractical to continue hydrogenation.

It is evident from the results expressed in the above table that when the Raney nickel catalyst is usedin amounts below the minimum ratio of one part of Raney nickel catalyst to two parts of substituted pyridine compound a practical and effective reduction can not be realized. The low degree of hydrogenation at that point at which further hydrogen adsorption becomes negligible, the extended period of time required to reach that point and the difficulty of separating the reduced product from the unreduced substituted pyridine compound make it impracticable to employ a process using amounts of Raney nickel catalyst below the ratio of one part of catalyst to two parts of substituted pyridine compound.

' 7 Having described my invention what I claim as new and desire to secure by Letters Patent is:

l-nA process for producing a substituted piperidine 'eoiripoiiiid having the formula 1 R N R 11 H wherein R is selected from the group consisting of hydrogen and methyl, ethyl, propyl, vinyl, propenyl, benzyl and 's'ty'ryl radicals, with the proviso that not more than one or the Rs is hydrogen, which comprises dissolving a substituted pyridine compound selected from the group "consisting of 2 and 6, and 2, 6 methyl, ethyl, propyl, vinyl, propenyl, benzyl and styryl substituted pyridine compounds and the acid salts thereof in a suitable volatile inert solvent and hydrogenating the substituted pyridine dissolved in the solvent in the presence of'at least about one 'p'art'of Raney nickel catalyst for each'two parts of the substituted pyridine compounds, saidhydrogenatio'n being effected at about room temperature andunder a hydrogen pressure of from about 2 to about 20 atmospheres.

2. The process of claim 1 wherein the hydrogenation is carried 'out on the substituted pyridine compound in the form of its free base and wherein the solvent is sele'cted from the group consisting of water, inert aliphatic alcohols, mixtures of Water and water-miscible aliphatic alcohols and inert hydrocarbon solvents.

3. The process of claim 2 wherein the substituted pyridine compound employed'is Z-methyl pyridine and the solvent is water.

'4. The process of claim 3 wherein at least about one part of Raney nickel catalyst is present for each part of 2-methyl pyridine, and wherein the hydrogenation is effected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

5. The process of claim 2 wherein the substituted pyridine compound employed is Z-methyl pyridine and the solvent is a hydrocarbon solvent.

"6. The process of claim 5 wherein at least about one parrot Raney nickel catalyst is present for each 'part 8 of Z-methyl pyridine, and wherein the hydrogenation is effected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

'7. The process of claim 2 wherein the substituted pyridine compound employed is 2-methyl pyridine and the solvent is toluene.

8. The process of claim 7 wherein at least one part of Raney nickel catalyst is present for each part of 2- methyl pyridine, and wherein the hydrogenation is elfected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

9. The process of claim 1 wherein the hydrogenation is carried out on the substituted pyridine compound in the form of its acid salt in an aqueous solution thereof.

10. The process of claim 9 wherein the substituted pyridine compound is2-methyl pyridine.

11. The process of claim 10 wherein at least about one part of Raney nickel catalyst is present for each part of Z-methyl pyridine, and wherein the hydrogenation is effected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

12. The process of claim 1 wherein the hydrogenation is carried out on the substituted pyridine compound in the form of its acid salt and the solvent is a lower inert aliphatic monohydric alcohol.

13. The process of claim 12 wherein the substituted pyridine compound is Z-methyl pyridine.

14. The process of claim 13 wherein at least about one part of Raney nickel catalyst is present for each part of Z-methyl pyridine, and wherein the hydrogenation is effected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

15. The process of claim 1 wherein the hydrogenation is carried out on the substituted pyridine compound in the form of its acid salt in an aqueous alcoholic solution thereof.

16. The process of claim 15 wherein the substituted pyridine compound is Z-me'thyl pyridine.

17. The process of claim 16 wherein at least about one part of Raney nickel catalyst is present for each part of Z-m'ethyl pyridine, and wherein the hydrogenation is effected at about room temperature and under a hydrogen pressure of from about 2 to about 5 atmospheres.

References Cited in the file of this patent Adkins et al.: JACS 70, 695 (1948). 

1. A PROCESS FOR PRODUCING A SUBSTITUTED PIPERIDINE COMPOUND HAVING THE FORMULA 